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CHILD AND ADOLESCENT SCHIZOPHRENIA
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CHILD AND ADOLESCENT SCHIZOPHRENIA S. Charles Schulz, MD, Robert L. Findling, MD, Alexandria Wise, BA, Lee Friedman, PhD, and John Kenny, PhD
Nineteenth-century psychiatrists, such as Morel and Kraeplin, focused on adolescent onset psychosis in their descriptions of dementia praecox, an illness they characterized with psychosis and poor outcome. Yet by the middle of the 20th century, psychosis in teenage years was often thought of as a phase of development or as a reaction to stress. This view of the illness schizophrenia in its early stages is underscored by the lack of research into both neuropsychiatric and pharmacologic research. Although childhood schizophrenia (onset before age 12) is considered rare, schizophrenia has its onset in patients before age 19 in nearly 40% of the cases of males and 23% in the case of females.39 Therefore, for clinical treatment, it is important for the field of psychiatry to become better acquainted with the early stages of the illness. In addition, recent neuropsychiatric research studies have indicated that patients with schizophrenia in adolescence may offer important clues to the cause of the illness because of important neurodevelopmental processes that occur during teenage years.29 This article consists of a review and a description of diagnostic and epidemiologic issues relating to child and adolescent schizophrenia. Next, current research focusing on brain imaging and neuropsychology is described and placed in a neurodevelopmental context. Then, the use of antipsychotic medications is described with attention paid to usage of new antipsychotic medication. The concluding section focuses on
From the Department of Psychiatry (SCS, RLF, AW, LF, JK), the Department of Pediatrics (RLF), Case Western Reserve University; and University Hospitals of Cleveland (SCS, RLF); and Cleveland Veterans Administration Medical Center (JK), Cleveland, Ohio
THE PSYCHIATRIC CLINICS OF NORTH AMERICA VOLUME 21 * NUMBER 1 * MARCH 1998
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psychosocial issues, especially the family’s response to the development of psychosis in their child. EPIDEMIOLOGY AND DIAGNOSIS
When objective criteria and scientific sampling methods are empl0yed,4~epidemiologic surveys have consistently shown that the prevalence of schizophrenia is 1%in the United States of America. Furthermore, in studies of the general population, schizophrenia is of equal prevalence in both genders. To understand the prevalence of schizophrenia in adolescents, studies of schizophrenia occurring in adults or in first-break studies are frequently examined to determine age of onset. For example, in the L ~ r a n g e rarticle ~ ~ alluded to in the introduction, all consecutive discharges from the hospital were examined to determine if males had an earlier age of onset than females. One hundred medical records of adult patients from each gender were examined for age of first treatment, age of first hospitalization, and age of first psychotic symptoms (family’s report). Examination of these results shows that males did have an earlier onset by an average of 5.4 years and that 39% of males had their first psychotic symptoms by age 19. For females, 23% had their first psychotic symptoms by 19 years age. In addition to examining the time of first symptoms, Loranger also noted age of first treatment and first hospitalization-an issue specifically addressed by Beiser et a13 and Hafner et al.25 While investigating first-episode patients to determine the reliability of ascertaining the prodromal phase of schizophrenia, Beiser and colleagues3noted that the average age of onset for all patients was before age 21 (even though first-break patients under 15 years of age were not examined). This study underscores the early onset of psychotic symptoms in schizophrenia. Beyond documenting early onset, the major question was the timing of the prodromal period and the age of first treatment. The group also demonstrated a significant treatment lag or the time between onset of first symptoms and treatment. The authors do note that first symptoms and first treatment can be reliably assessed and then go on to note a median of 52.7 weeks of prodrome and 8.2 weeks of treatment lag for schizophrenia. The means for both measures were longer (112.8 weeks for prodrome and 56.1 weeks for treatment lag)-a finding the authors attribute to a number of patients who had exceedingly long values. The long mean treatment lag of approximately one year may have meaningful clinical applications that is discussed in the section on pharmacology. Hafner et al,25 also explored the phases of onset for first-episode patients and corroborates the findings of Beiser et a1,3 noting both an earlier onset in males and lengthy prodromes. Interestingly, in follow-up studies of childhood-onset schizophrenia, Eggers and BunkI2 do not find an earlier age of onset for males in the prepubescent patients they studied. Therefore, the onset of males before
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females may be a phenomenon of adolescent and early adult illnessperhaps because of the possible protective influence of estrogen, as discussed by the authors of the study. Diagnostic issues have played a major role in schizophrenia, with increased reliability coming from the Diagnostic and Statistical Manual of Mental Disorders, ed 3 (DSM-III).*However, even with objective atheoretical criteria, many professionals felt that the diagnosis of schizophrenia was difficult in children and adolescents. Key diagnostic issues were related to the ability to distinguish schizophrenia from bipolar illness and the ability to assess symptoms in adolescents reliably. The concern was that criteria for the diagnosis of schizophrenia in adults did not directly apply to children and adolescents. The differential diagnostic issue in young people had been compounded by the reported confusion of making an accurate assessment of schizophrenia versus bipolar disorder in adolescents.8 This original report demonstrated the overdiagnosis of schizophrenia in psychotic teenagers and pointed to the patient’s better outcome with lithium compared with their initial treatment with antipsychotic medications. This report appears to have led to more careful assessment of psychosis in teenagers, and perhaps a reluctance to use antipsychotics in adolescent patients. An assessment of current studies of the phenomenology of psychotic illnesses in adolescents indicates that for both childhood-onset and adolescent cases of schizophrenia, the same symptoms noted in adults are present. For example, in Spencer and Campbell’s54pharmacotherapy study of childhood schizophrenia, 100% of the youngsters in the project had either hallucinations or delusions or both. Previously, Russell et a150 had also pointed to the finding that children experience and report the same positive symptoms of schizophrenia as do adults. McKenna, et a143reviewed the first 71 cases of presumed schizophrenia referred to the National Institute of Mental Health (NIMH) for admission to research studies. Their major point was that there is excellent diagnostic agreement between research clinicians concerning diagnosis of psychotic disorders. For schizophrenia, the agreement was highly statistically significant. Another point emerged from their analysis of diagnosis-a number of presumed schizophrenic young people did not meet diagnostic criteria, but were reliably assessed as having multidimensional impaired disorder. Even though numerous current investigators note the ability to utilize objective diagnostic criteria in children and adolescents, not all psychotic disorders fulfill criteria for schizophrenia. Carlson, et a17 now have reported on the reliability of assessing psychosis in young people, although her group’s sample is a firstepisode patient group with only a portion being teenagers. In an assessment of all first-episode hospitalized psychotic patients, the identification of psychotic symptoms was reliably assessed. In the most recent study of first-episode patients, the authors point out that in the 1990s,
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community-based clinicians accurately make the differential diagnosis between schizophrenia and bipolar illness. Outcome studies can lead to important clinical as well as scientific data about schizophrenia. In a study of adolescent inpatients, Welner and colleagues61were able to assess 13 schizophrenic patients from a larger general population and to note a generally severe outcome. Of the 13 schizophrenic patients, 2 had committed suicide in the 8 to 10year follow-up period. In the remaining 11, social relationships did not develop well and vocational functions were invariably poor. These findings, although on a very small sample, point to a hypothesis of poorer outcome in this early onset group. In a larger sample studied by Krausz and Miller-Th~msen~~ in Germany, adolescent-onset patients were assessed at 5 and 11 years. Many were judged to have continuous illness and required substantial care. Of importance for clinicians was the finding that anxiety and suicidality were substantial issues of morbidity. In this report, a gender difference in adolescents was found, as females had a better outcome than males. In a recently published, long-term outcome study of childhood onset schizophrenia, Eggers and BunkI2 report on a 2-year follow-up study. This current report is the second follow-up assessment by the investigators and describes some interesting points for clinicians and researchers. Overall, the general outcome for the childhood-onset patients was poor, for example, 50% of patients were judged to poorly remitted. On the other hand, 25% were noted to be completely remitted. In their paper, insidious onset was significantly associated with poorer outcome, with none of the insidious-onset patients having a remitted outcome. NEUROPSYCHIATRIC RESEARCH
Noninvasive methods for studying brain structure and function have led to an increased but still a small body of research in the early stages of schizophrenia. Briefly stated, structural brain imaging in adults with schizophrenia have shown increased size of ventricles when compared with nonschizophrenic adult controls. This was originally reported by Johnstone et a130 and reviewed in metaanalysis by Elkis et al,I3 and decreased brain volume (see Ward et a158for review). Also, in adults, follow-up scanning studies have shown that ventricle size does not change over periods of 1-5 years.44,27 However, in the last year, studies of first-break young adultsl0 and childhood-onset schizophrenia patient~ have ~ ~ shown subtle changes in ventricular size during the followup period. As noted in the introduction, the neuropsychiatric study of schizophrenia during adolescence may add to a better understanding of the disease because of important neurodevelopmental events that occur during this period. Further, as more studies are performed, those in the field may learn about specific clinically relevant issues related to schizophrenic teenagers.
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Beginning with brain imaging in adolescents Schulz et al5I decided to approach the issue of onset of ventricular enlargement in schizophrenia by using CT and compared ventricular brain ration (VBR) in patients with that of medical controls and personality disorder patients. The teenage schizophrenic patients, who had an average age of 16 years and had been ill for less than 2 years, had greater VBR compared with both medical record controls and borderline personality patients. Following an analysis by Weinberger et a160 in which they demonstrated that ventricular size was not related to the length of illness, Schulz et a151showed that VBR in teenagers was not related to how long an adolescent patient had been ill. This finding supports the neurodevelopmental hypothesis of schizophrenia as opposed to a neurodegenerative theory in the younger patient group. Research in schizophrenia at the time of CT studies focused on correlates of increased VBR. For example, enlarged VBR was associated with low levels of neuropsychologic function2*and with poor premorbid adjustment.” To pursue this theme of research in adolescents, Jennings et alZ8showed that VBR in teenagers was statistically significantly inversely correlated with metabolites of dopamine (HVA-homovanillic acid) and serotonin (5HIAA-5 hydroxyindole acetic acid), as had been demonstrated by Potkin et a146in adult patients. Also, and of possible clinical relevance, adolescent schizophrenic patients who had enlarged ventricles showed poorer response to antipsychotic medication treatment than adolescents who had ventricles of similar size to the adolescents in the control Note that there are many reports of the relationship of treatment response and brain-imaging parameters-some note a statistical relationship, whereas others do not. Friedman et all9 have done a complete metaanalysis of brainscan studies and neuroleptic treatment outcome and have demonstrated that the relationship is not universal. However, when the illness duration and age of onset were examined, there was a relationship of effect size in the VBR-treatment response correlation. Friedman and colleague^^^ speculate that early stages of schizophrenia may be a time of the illness when brain structure and pharmacologic treatment response are related. With the emergence and availability of MR imaging, our group and that of the NIMH Intramural Program (Dr Judith Rapoport) embarked on studies of adolescent patients. Although each group had examined teenage patients, the NIMH group has focused on childhood-onset patients while the Case Western Reserve University (CWRU) group has studied an adolescent clinical sample from local referrals. From NIMH, Frazier et all6 demonstrated a smaller brain volume and smaller midsagittal thalamic area in the 21 patients compared with the 33 nonpatient controls. Interestingly, the childhood-onset patients had larger VBR than controls, but the difference did not reach statistical significance ( P = 0.06). The authors comment on the importance of studying childhood-onset schizophrenia as it may be a more severe form of the illness and thus biological leads may be more clearly and homogeneously seen. The results outlined in this paper also led the authors to reaffirm their ideas of the continuum of schizophrenia across age groups.
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After the publication of this paper, Dr. Rapoport presented fascinating data on a 2-year follow-up of the childhood-onset group, who were first scanned at age 14.47Interestingly, during the 2-year follow-up, it was revealed that there was a slight but significant increase in the ventricular volume of the childhood-onset group when compared with individuals in the control group. This is all the more remarkable because the patients were not at the beginning of their illness-a time when it seems more likely that structural changes could occur. These results point to the possibility of dynamic changes occurring during adolescence-a finding that deserves closer research attention. The CWRU group has been studying a sample of adolescents who have schizophrenia and who had been referred by local clinicians who then participate in MR imaging structural studies, neuropsychologic assessment, and smooth pursuit-eye tracking studies. All are clinically stabilized on medication of the clinician's choice and receive a diagnostic assessment with structured interviews. The control group was carefully assembled from the community and underwent similar assessments and studies. The MR imaging and the neuropsychology studies that have been presented to date are described. Friedman and colleagues18have presented results of the group's initial MR imaging work with the adolescent schizophrenic patients. The most robust finding was the reduced brain volume index noted in the schizophrenic patients. In the Friedman report, similar to the findings of Frazier et a1,16VBR was not different between the schizophrenic patients and the individuals in the control group, but the VBR measures were numerically equivalent. Assessment of the control group showed wide variability, thus pointing to the importance of methodology in collecting normal samples, as has been discussed by Iacono et a1.26The reduced brain volume finding is consistent with the results of a recent metaanalysis of brain volume that shows a significant reduction of volume across Structural brain studies are an important way to assess the central nervous system in schizophrenia, but they do not directly address function. Kenny et a135reported on the neuropsychologicalresults in the same teenage sample. They noted decreased neuropsychologic performance in the areas of attention, recall, and memory. Interestingly, the patients were not abnormal on all tests. The investigators went on to examine the data, controlling statistically for IQ and attention, and the differences remained, even though the patients had numerically lower IQ scores. Previous studies had pointed to reduced neuropsychologic performance in teenagers-studies such as those by Goldberg et a1,2O which demonstrated significant differences in both verbal and performance IQs in schizophrenic adolescents, pointing to low neuropsychologic performance in this young population. These findings are consistent with the emerging literature, demonstrating either neuropsychologic or neuromotoric differences or both between youngsters who become schizophrenic and youngsters who do not develop schizophrenia used as controls.32 Such findings coupled with neuropsychologic results in young-adult
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first-episode patients4 make Kenny and colleague'^^^ current study in adolescents consistent with results in adults. These imaging and neuropsychologic findings have important implications for the current hypotheses about the pathophysiology of schizophrenia. One of the current and compelling theories of the pathophysiology of schizophrenia is the neurodevelopmental hypothesis.57,59 The theory posits that a lesion (an abnormality, not necessarily, spaceoccupying tissue) interacts with the developing brain. This theory is consistent with an increased VBR, a general lack of gliosis, and a lack of progression of brain-imaging findings (i.e., progressive enlargement of ventricles). The findings of Friedman et all8 and Frazier et all6 of decreased brain volume supports the characteristics of a neurodevelopmental versus a neurodegenerative illness, especially when seen without increase in ventricular size. The CWRU group, however, has not conducted systematic follow-up imaging studies that would assess possible structural changes. Note, as reported by Rapoport et a147the findings that subtle ventricular changes are seen over 2 years. Therefore, the research study of schizophrenia in patients under age 18 can offer unique opportunities for understanding the neurodevelopmental hypothesis. Also, as follow-up studies progress, those in the field can learn if earlyonset disease is more severe as measured by brain imaging. PHARMACOTHERAPY
As noted in previous reviews,15there is a paucity of empiric studies of medication treatment for schizophrenia in adolescents. In children and adolescents, there are 2 placebo-controlled trials45,54 that demonstrate that the traditional antipsychotic medications are effective compared with placebo and that, as expected, positive symptoms are reduced. There is one study using objective ratings that compares two traditional antipsychotic medications-thiothixene and thioridazine,48 and that demonstrates a decrease in psychotic symptoms. An interesting clinical note in Realmuto and colleague^^^ work is the observation of the high rate of neuroleptic intolerant patients-those patients who had intolerable side effects at doses below what would be considered an adequate trial. For many reasons, including efficacy in adult patients and lower movement side effects, investigators have been examining new or atypical antipsychotic medications in adolescents. As expected, early reports were case studies showing the safety and effectiveness of ri~peridone.~~ For this early risperidone case series, the authors note effectiveness in schizophrenia as well as other psychotic disorders. They further suggest that risperidone may help adolescents who were not helped by traditional antipsychotic medications. However, clinicians need to be aware that there is not a controlled trial of the usefulness of risperidone in adolescent nonresponders, although Bondolfi, et a15 have shown the usefulness of risperidone in adult nonresponders.
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Grcevich and colleague^^^ at CWRU recently published a larger case series (N = 16) assessing risperidone treatment in adolescents. In this report, the total BPRS as well as the negative symptom items were both reduced. They found that the medication was well accepted by the young patients, a phenomenon not seen with traditional antipsychotics (note earlier comments re: Realmuto et a1 studys). Note that the Grcevich et alZ3study was started shortly after risperidone was made available so that doses of 6 mg/day were considered routine. Since the completion of the study, our group begins at low doses of risperidone and increases the dose slowly-many of our patients are managed with 3 mg/day. In relation to dosing strategies used for young patients, Kapur and coll e a g u e ~have ~ ~ reported clinical success using haloperidol at a dose of 2 mg/day in first-episode patients. Haloperidol 2 mg leads to high-dopamine receptor blockade as measured by positron emission tomography (PET). Noted that, although there is enthusiasm for the use of risperidone in children and adolescents, Mandoki40 has reported that he frequently saw extrapyramidal symptoms (EPS) in patients having a variety of psychiatric disorders and who were given risperidone. Also, dystonia and galactorrhea were seen. Therefore, it is prudent for clinicians to be aware of these side effects and to follow reports of atypical antipsychotics to be knowledgeable about their safety. Clozapine has been available for many years following the report from Kane et a133 on its usefulness as a treatment for patients who were not responsive to traditional antipsychotic medication treatment. Clozapine is also used for patients who are intolerant to traditional antipsychotic medications and for those who have developed tardive dy~kinesia.~~ The use of clozapine in patients who are under 18 has not received much attention in the literature, perhaps because of the agranulocytosis side effect or general concerns about using a last-resort medication in young people. However, NIMH has explored the use of clozapine in its childhood-onset sample in two distinct studies. The first was a report on the effectiveness and safety in an open trial lasting 6 weeks in which 11 adolescents with childhood-onset schizophrenia were studied.17 The patients had not done well with traditional antipsychotic medication; however, with clozapine, half showed a marked improvement. The authors note that all 11 patients were discharged on clozapine. The mean dose for this group, whose average age was 14.0, was 370 mg/ day-comparable with or slightly lower than doses used in adult clinics. In this open report, the authors note that clozapine was generally well tolerated with side effects being similar to what would be expected in adults. From the same group, Kumra et a137published the results of a double-blind, haloperidol-controlled trial in childhood-onset patients ( n =21) who were approximately 14 years old at the time of the trial. Clozapine showed clear statistical advantages over haloperidol on measures of psychosis. However, in some contrast to their open-label report,
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one third of the patients had clozapine discontinued-both neutropenia and seizures were the most significant concerns. An open-label study from Israel56of clozapine showed improvement in positive and negative symptoms of schizophrenia in a childhoodonset group. Interestingly, a lower dose of medication-mean dose of 227 mg/day compared with 370 mg/day-was used in this young group as reported by Frazier et al.17 The overall report was positive and no agranulocytosis was noted. Perhaps strategies to reach the lowest effective dose of clozapine could lead to successful treatment with few side effects. Preliminary reports indicate that tardive dyskinesia (TD) may be seen less frequently with risperidone6 and with the potential for low TD with olanzapine exists based on early ~tudies.’~” As young people diagnosed as schizophrenic may be exposed to antipsychotic medication for many years, these two new medications may reduce the risk of TD when used as the first treatment. There are important issues related to pharmacotherapy that have been brought into focus by studies of first-break schizophrenic patients and that have a bearing on the treatment of adolescent schizophrenic patients. Johnstone et aP1 noted an association between the length of time a patient was ill and their course following initial treatment. This report was followed by the assessment by Loebel et a138of the relationship between the length of time a patient had been ill and the treatment response in the Hillside first-episode study. The reports build on earlier follow-up studies. One study was done by May et a141and it showed an increase in hospital days for patients assigned to placebo as opposed to those who were assigned to medication, and the other was a review by Wyatt62in which the issues of early medication use and outcome were discussed. For children and adolescents who have schizophrenia, if a chronic course is to be avoided, it may be important to be more assertive in beginning medication treatment than was thought in the past. It can be hoped that the new, atypical antipsychotic medications will allow for a better and safer start with treatment. FAMILY ISSUES
Over the past 20 years, many paper^'^,^^ have noted an improvement in patient outcome, usually measured in reduced relapse rates, when family therapy is part of the treatment regimen. Review of the family therapy studies reveals that most interventions are based on a psychoeducational and supportive model such as those described by Anderson’ and M ~ F a r l a n e Therefore, .~~ one would reason that such interventions could help childhood-onset and adolescent schizophrenic patientsmaybe especially, because they are generally living at home. Interestingly, there is little empiric literature that addresses family concerns (or burdens) of this patient age group. Also, there are no empiric trials, comparable with adult studies, that provide assistance in
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how to proceed with family psychoeducational programs for adolescent patients. We were struck by the families’ response to the onset of psychosis in their adolescent children as we began working with them in our adolescent brain-imaging project. Somewhat unlike families of adult patients, these younger families responded (in general) with shock, denial, and anger. These responses are, perhaps, more similar to a family’s response to a serious medical illness. To address this issue, Davies9 has reported on preliminary results of data gathered from over 50 family members who have an adolescent who has a serious psychiatric illness. She reported substantial burden that, unsurprisingly, was not evident among all families. They conclude that assessment of burden and a family’s own difficulties (i.e., with depression) can lead to specific treatment planning for the family. It goes without saying that studies with appropriate controls are needed to develop the most constructive treatment approaches.
CONCLUSION
In this article from a neuropsychiatric viewpoint, attention has been drawn to issues facing patients who have schizophrenia. Therefore, it contains descriptions of studies that illustrate the frequency of schizophrenia before adulthood. The view is that, although childhood-onset of schizophrenia may be rare, adolescent-onset schizophrenia is not. Perhaps because adolescents quickly become adult patients, less attention has been focused on developing empiric neurobiologic studies for this patient group. However, as has been noted in the work by NIMH, the younger-onset patient group may offer scientific opportunities because they are hypothesized to be a more homogenous subtype of schizophrenia. Also, the follow-up studies-the few that have been performedshow that early-onset patients may be more severely ill than adult-onset patients, thus clinicians need more information on the characteristics of the child and the adolescent group. The studies cited in the section on brain-imaging demonstrate that brain morphometric differences from controls-smaller brain volume, for example-are present in the adolescent group. Researchers studying this population indicate that this adds to theories that childhood and adolescent schizophrenia are on a continuum with the adult disorders, not a separate illness. Most recently though, Delisi et all0 and Rapoport et a147have indicated that there may be morphometric changes at first break and in childhood-onset schizophrenia. Thus, studies of adolescents when important brain developments events occur gain new importance. Neuropsychology studies have considerably added to the understanding of those in the field of adult schizophrenia-both in characterization and in relationship to functional outcome.24In a report by Kenny et aP5 it was demonstrated that brain function-as assessed by neuro-
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psychology-is poorer in teenage patients. Such studies can help investigators understand schizophrenia better by charting neuropsychologic measures through the life cycle, and this may hold greater importance for clinicians. As expected, not all adolescents have the same neuropsychologic deficits so that understanding which deficits are prominent may lead to improved treatment planning. New, atypical antipsychotic medications may have much to offer adolescent patients, and we have noted the preliminary studies exploring both clozapine and risperidone. Our view is that the new drugs may treat psychosis with fewer side effects than seen with traditional antipsychotics, thus allowing for a better start with treatment. Despite enthusiasm for new treatments, there is still little empiric work on their use, so caution is still advised. We note the accumulating evidence of the relationship between length of time before treatment and outcome and urge clinicians to help young people get started with pharmacotherapy more quickly after the onset of psychosis. The focus on neuropsychiatric parameters does not exclude the importance of family treatment both to diminish their own distress and to improve the patient’s outcome. However, we must note that little of the work performed with adult patients and their families has found its way into the research on adolescents. Our impression has been that young families have distinct needs as they face the shock of onset of a psychotic illness in the family. In conclusion, we have aimed to describe the epidemiology, diagnostic factors, neurobiologic characteristics and treatment considerations for childhood and adolescent schizophrenic patients. We think we have demonstrated the existence of compelling evidence for continuity in phenomenology and pathophysiology between adolescent and adult stages of the illness and the importance of early intervention. Clearly, this is an emerging area of schizophrenia research and program development so that those interested in these young patients have much to look forward to in upcoming literature. References 1. Anderson C: A psychoeducational program for families of patients with schizophrenia. In McFarlane WR (ed): Family Therapy in Schizophrenia. New York, Guilford Press, 1983 2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 3. Washington, DC, American Psychiatric Association, 1980 3. Beiser M, Erickson D, Fleming JAE, et al: Establishing the onset of psychotic illness. Am J Psychiatry 150:1349-1354, 1993 4. Bilder RM, Lipschutz-Broch L, Reiter G, et al: Intellectual deficits in first-episode schizophrenia: Evidence for progressive deterioration. Schizophr Bull 18:437448,1992 5. Bondolfi G, Bauman P, Petris M, et al: A randomized double-blind trial of risperidone versus clozapine for treatment-resistant chronic schizophrenia. 151st Annual Meeting of the American Psychiatric Association, Miami, May 1995 6. Brecher MB: Long-term safety of risperidone [abstract NR3771. New Research Annual Meeting of the American Psychiatric Association, New York, 1996, p 170
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7. Carlson GA, Fennig SD, Bromet E: The confusion between bipolar disorder and schizophrenia in youth: Where does it stand in the 1990s? J Am Acad Child Adolesc Psychiatry 33:453460, 1994 8. Carlson GA, Strober M: Manic depressive illness in early adolescence: A study of clinical and diagnostic characteristics in six cases. J Am Acad Child Adolesc Psychiatry 2511-525, 1978 9. Davies MA: Parents of teenagers with psychosis. Annual Meeting of the American Psychiatric Association, San Diego, 1997, p 2 10. DeLisi LE, Sakuma M, Tew W, et al: Schizophrenia as a chronic active brain process: A study of progressive brain structural change subsequent to the onset of schizophrenia. Psychiatry Res Neuro 74:129-140, 1997 11. Donnelly EF, Weinberger DR, Waldman IN, et al: Cognitive impairment associated with morphological brain abnormalities on computed tomography in chronic schizophrenic patients. J Nerv Ment Dis 168:305-308, 1980 12. Eggers C, Bunk D The long-term course of childhood-onset schizophrenia: A 42-year follow-up. Schizophr Bull 23:105-117, 1997 13. Elkis H, Friedman L, Wise A, et al: Meta-analyses of studies of ventricular enlargement and cortical sulcal prominence in mood disorders. Comparison with controls or patients with schizophrenia. Arch Gen Psychiatry 52:735-746, 1995 14. Falloon IR, Boyd JL, McGill CW, et al: Family management in the prevention of exacerbations of schizophrenia: A controlled study. N Engl J Med 3061437-1440,1982 15. Findling RL, Grcevich SJ, Lopez I, et a1 Antipsychotic medications in children and adolescents. J Clin Psychiatry 57(suppl 9) :19-23, 1996 16. Frazier JA, Giedd JN, Hamburger SD, et al: Brain anatomic magnetic resonance imaging in childhood-onset schizophrenia. Arch Gen Psychiatry 53:617-624, 1996 17. Frazier JA, Gordon CT, McKenna K, et al: An open trial of clozapine in 11 adolescents with childhood-onset schizophrenia. J Am Acad C h l d Adolesc Psychiatry 33:658663, 1994 18. Friedman L, Findling RL, Buck J, et al: Structural MRI and neuropsychological assessments in adolescent patients with either schizophrenia or affective disorders. Schizophr Res 18:189-190, 1996 19. Friedman L, Lys C, Schulz SC: The relationship of structural brain imaging parameters to antipsychotic treatment response: A review. J Psychiatry Neurosci 1742-54, 1992 19a. Gao X, Sakai K, Tamminga CA: Chronic treatment of rats with sertindole and olanzapine produce low rates of oral dyskinesias. Schizophr Res 24:270, 1997 20. Goldberg TE, Karson CN, Leleszi JP, et al: Intellectual impairment in adolescent psychosis: A controlled psychometric study. Schizophr Res 1:261-66, 1988 21. Golden CJ, Moses JA, Jr, Zelazowski R, et al: The relationship of cerebral ventricular size and neuropsychological impairment as measured by the standardized Luria neuropsychological battery in young chronic schizophrenics. Arch Gen Psychiatry 37619-623, 1980 22. Goldstein MJ, Rodnick EH, Evans JR, et al: Drug and family therapy in the aftercare of acute schizophrenics. Arch Gen Psychiatry 351169-1177, 1978 23. Grcevich SJ, Findling RL, Rowane WA, et al: Risperidone in the treatment of children and adolescents with schizophrenia: A retrospective study. J Child Ado1 Psychopharmacol 6:251-257, 1996 24. Green M F What are the functional consequences of neurocognitive deficits in schizophrenia? Am J Psychiatry 153:321-330, 1996 25. Hafner H, Maurer K, Loffler W, et al: The influence of age and sex on the onset and early course of schizophrenia. Br J Psychiatry 162S0-86, 1993 26. Iacono WG, Smith GN, Moreau M, et al: Ventricular and sulcal size at the onset of psychosis. Am J Psychiatry 145:820-824, 1988 27. Illowsky BP, Juliano DM, Bigelow LB, et al: Stability of CT scan findings in schizophrenia: Results of an 8-year followup study. J Neurol Neurosurg Psychiatry 56:209-213, 1988 28. Jennings WS, Schulz SC, Narasimhachari N, et al: Brain ventricular size and CSF monoamine metabolites in an adolescent inpatient population. Psychiatry Res 16:8794, 198.5
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29. Jemigan TL, Tallal P: Late childhood changes in brain morphology observable with MRI. Dev Med Child Neurol 32:379-385, 1990 30. Johnstone EC, Crow TJ, Frith CD, et al: Cerebral ventricular size and cognitive impairment in chronic schizophrenia. Lancet 2924-926, 1976 31. Johnstone EC, Macmillan JF, Frith CD, et a1 Further investigation of the predictors of outcome following first schizophrenic episodes. Br J Psychiatry 157182-189, 1990 32. Jones P, Rogers B, Murray R, et a1 Child developmental risk factors for adult schizophrenia in the British 1946 birth cohort. Lancet 344:1398-1402, 1994 33. Kane J, Honigfeld G, Singer J, et al: Clozapine for the treatment-resistant schizophrenic: A double-blind comparison with chlorpromazine. Arch Gen Psychiatry 45:789-796, 1988 34. Kapur S, Remington G, Jones C, et al: High levels of dopamine D, receptor occupancy with low-dose haloperidol treatment: A PET study. Am J Psychiatry 153:948-950,1996 35. Kenny JT, Friedman L, Findling RL, et al: Cognitive impairment in adolescent schizophrenia. Am J Psychiatry 154:1613-1615, 1997 36. Krausz M, Muller-Thomsen T Schizophrenia with onset in adolescence: An 11-year follow-up. Schizophr Bull 19:831-841, 1993 37. Kumra S, Frazier JA, Jacobsen LK, et a1 Childhood-onset schizophrenia: A doubleblind clozapine-haloperidol comparison. Arch Gen Psychiatry 53:1090-1097, 1996 38. Loebel AD, Lieberman JA, Jose MJ, et a1 Duration of psychosis and outcome in firstepisode schizophrenia. Am J Psychiatry 149:1183-1188, 1992 39. Loranger AW: Sex difference in age of onset of schizophrenia. Arch Gen Psychiatry 41:157-161, 1984 40. Mandoki MW Risperidone treatment of children and adolescents: Increased risk of extrapyramidal side effects? J Child Adolesc Psychopharmacol 5:49-67, 1995 41. May PR, Tuma AH, Yale C, et al: Schizophrenia: A follow-up study of results of treatment. 11. Hospital stay over two to five years. Arch Gen Psychiatry 33:481486, 1976 42. McFarlane WR Multiple family therapy in schizophrenia. In McFarlane WR (ed): Family Therapy in Schizophrenia. New York, Guilford Press, 1983 43. McKenna K, Gordon CT, Lenane M, et al: Looking for childhood-onset schizophrenia: The first 71 cases screened. J Am Acad Child Adolesc Psychiatry 22:636-644, 1994 44. Nasrallah HA, Olson SC, McCalley-Whitters M, et al: Cerebral ventricular enlargement in schizophrenia: A preliminary follow-up study. Arch Gen Psychiatry 43:157159, 1986 45. Pool D, Bloom W, Mielke DH, et al: A controlled evaluation of Loxitane in seventyfive adolescent schizophrenic patients. Curr Ther Res Clin Exp 19:99-104, 1976 46. Potkin SG, Weinberger DR, Linnoila M, et al: Low CSF 5-hydroxyindoleacetic acid in schizophrenics with enlarged ventricles. Am J Psychiatry 140:21, 1983 47. Rapoport JL, Giedd J, Alaghband-Rad J, et al: Accelerated increase brain ventricular volume at 2-year rescan for childhood onset schizophrenics [abstract]. Schizophr Research 24154, 1997 48. Realmuto GM, Erickson WD, Yellin AM, et al: Clinical comparison of thiothixene and thioridazine in schizophrenic adolescents. Am J Psychiatry 141:440-442, 1984 49. Regier DA, Boyd JH, Burke JD, et al: One-month prevalence of mental disorders in the United States. Arch Gen Psychiatry 45:977-986, 1988 50. Russell AT, Bott L, Sammons C: The phenomenology of schizophrenia occurring in childhood. J Am Acad Child Adolesc Psychiatry 28:399407, 1989 51. Schulz SC, Koller MM, &shore PR, et al: Ventricular enlargement in teenage patients with schizophrenia spectrum disorder. Am J Psychiatry 140:1592-1595, 1983 52. Schulz SC, Sinicrope P, Kishore P, et al: Treatment response and ventricular brain enlargement in young schizophrenic patients. Psychopharmacol Bull 19:510-512,1983 53. Simeon JG, Carrey NJ, Wiggins DM, et a1 Risperidone effects in treatment-resistant adolescents: Preliminary case reports. J Child Adolesc Psychopharmacol5:69-79,1995 54. Spencer EK, Campbell M Children with schizophrenia: Diagnosis, phenomenology, and pharmacotherapy. Schizophr Bull 20:713-725, 1994 55. Tamminga CA, Thaker GK, Moran M, et al: Clozapine in tardive dyskinesia: Observa-
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tions from human and animal model studies. J Clin Psychiatry 55(suppl ~102-106, 1994 Turetz M, Mozes T, Toren P, et al: An open trial of clozapine in neuroleptic-resistant childhood-onset schizophrenia. Br J Psychiatry 170:507-510, 1997 Waddington JL, Buckley P F Neuroscience Intelligence Unit. The Neurodevelopmental Basis of Schizophrenia. Austin, Texas, R.G. Landes Co., 1996 Ward KE, Friedman L, Wise A, et a1 Meta-analysis of brain and cranial size in schizophrenia. Schizophr Res 22197-213, 1996 Weinberger DR Implications of normal brain development for the pathogenesis of Schizophrenia. Arch Gen Psychiatry 44:660-669, 1987 Weinberger DR, Torrey EF, Neophytides AN, et al: Lateral cerebral ventricular enlargement in chronic schizophrenia. Arch Gen Psychiatry 36:935-939, 1979 Welner A, Welner Z , Fishman R Psychiatric adolescent inpatients: Eight- to ten-year follow-up. Arch Gen Psychiatry 36:69&700, 1979 Wyatt RJ: Neuroleptics and the natural course of schizophrenia. Schizophr Bull 17325-351, 1991
Address reprint requests to S. Charles Schulz, MD Professor and Chairman Department of Psychiatry University Hospitals of Cleveland 11100 Euclid Ave Cleveland, OH 44106
SCHIZOPHRENIA
+ .OO
CHILD AND ADOLESCENT SCHIZOPHRENIA S. Charles Schulz, MD, Robert L. Findling, MD, Alexandria Wise, BA, Lee Friedman, PhD, and John Kenny, PhD
Nineteenth-century psychiatrists, such as Morel and Kraeplin, focused on adolescent onset psychosis in their descriptions of dementia praecox, an illness they characterized with psychosis and poor outcome. Yet by the middle of the 20th century, psychosis in teenage years was often thought of as a phase of development or as a reaction to stress. This view of the illness schizophrenia in its early stages is underscored by the lack of research into both neuropsychiatric and pharmacologic research. Although childhood schizophrenia (onset before age 12) is considered rare, schizophrenia has its onset in patients before age 19 in nearly 40% of the cases of males and 23% in the case of females.39 Therefore, for clinical treatment, it is important for the field of psychiatry to become better acquainted with the early stages of the illness. In addition, recent neuropsychiatric research studies have indicated that patients with schizophrenia in adolescence may offer important clues to the cause of the illness because of important neurodevelopmental processes that occur during teenage years.29 This article consists of a review and a description of diagnostic and epidemiologic issues relating to child and adolescent schizophrenia. Next, current research focusing on brain imaging and neuropsychology is described and placed in a neurodevelopmental context. Then, the use of antipsychotic medications is described with attention paid to usage of new antipsychotic medication. The concluding section focuses on
From the Department of Psychiatry (SCS, RLF, AW, LF, JK), the Department of Pediatrics (RLF), Case Western Reserve University; and University Hospitals of Cleveland (SCS, RLF); and Cleveland Veterans Administration Medical Center (JK), Cleveland, Ohio
THE PSYCHIATRIC CLINICS OF NORTH AMERICA VOLUME 21 * NUMBER 1 * MARCH 1998
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psychosocial issues, especially the family’s response to the development of psychosis in their child. EPIDEMIOLOGY AND DIAGNOSIS
When objective criteria and scientific sampling methods are empl0yed,4~epidemiologic surveys have consistently shown that the prevalence of schizophrenia is 1%in the United States of America. Furthermore, in studies of the general population, schizophrenia is of equal prevalence in both genders. To understand the prevalence of schizophrenia in adolescents, studies of schizophrenia occurring in adults or in first-break studies are frequently examined to determine age of onset. For example, in the L ~ r a n g e rarticle ~ ~ alluded to in the introduction, all consecutive discharges from the hospital were examined to determine if males had an earlier age of onset than females. One hundred medical records of adult patients from each gender were examined for age of first treatment, age of first hospitalization, and age of first psychotic symptoms (family’s report). Examination of these results shows that males did have an earlier onset by an average of 5.4 years and that 39% of males had their first psychotic symptoms by age 19. For females, 23% had their first psychotic symptoms by 19 years age. In addition to examining the time of first symptoms, Loranger also noted age of first treatment and first hospitalization-an issue specifically addressed by Beiser et a13 and Hafner et al.25 While investigating first-episode patients to determine the reliability of ascertaining the prodromal phase of schizophrenia, Beiser and colleagues3noted that the average age of onset for all patients was before age 21 (even though first-break patients under 15 years of age were not examined). This study underscores the early onset of psychotic symptoms in schizophrenia. Beyond documenting early onset, the major question was the timing of the prodromal period and the age of first treatment. The group also demonstrated a significant treatment lag or the time between onset of first symptoms and treatment. The authors do note that first symptoms and first treatment can be reliably assessed and then go on to note a median of 52.7 weeks of prodrome and 8.2 weeks of treatment lag for schizophrenia. The means for both measures were longer (112.8 weeks for prodrome and 56.1 weeks for treatment lag)-a finding the authors attribute to a number of patients who had exceedingly long values. The long mean treatment lag of approximately one year may have meaningful clinical applications that is discussed in the section on pharmacology. Hafner et al,25 also explored the phases of onset for first-episode patients and corroborates the findings of Beiser et a1,3 noting both an earlier onset in males and lengthy prodromes. Interestingly, in follow-up studies of childhood-onset schizophrenia, Eggers and BunkI2 do not find an earlier age of onset for males in the prepubescent patients they studied. Therefore, the onset of males before
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females may be a phenomenon of adolescent and early adult illnessperhaps because of the possible protective influence of estrogen, as discussed by the authors of the study. Diagnostic issues have played a major role in schizophrenia, with increased reliability coming from the Diagnostic and Statistical Manual of Mental Disorders, ed 3 (DSM-III).*However, even with objective atheoretical criteria, many professionals felt that the diagnosis of schizophrenia was difficult in children and adolescents. Key diagnostic issues were related to the ability to distinguish schizophrenia from bipolar illness and the ability to assess symptoms in adolescents reliably. The concern was that criteria for the diagnosis of schizophrenia in adults did not directly apply to children and adolescents. The differential diagnostic issue in young people had been compounded by the reported confusion of making an accurate assessment of schizophrenia versus bipolar disorder in adolescents.8 This original report demonstrated the overdiagnosis of schizophrenia in psychotic teenagers and pointed to the patient’s better outcome with lithium compared with their initial treatment with antipsychotic medications. This report appears to have led to more careful assessment of psychosis in teenagers, and perhaps a reluctance to use antipsychotics in adolescent patients. An assessment of current studies of the phenomenology of psychotic illnesses in adolescents indicates that for both childhood-onset and adolescent cases of schizophrenia, the same symptoms noted in adults are present. For example, in Spencer and Campbell’s54pharmacotherapy study of childhood schizophrenia, 100% of the youngsters in the project had either hallucinations or delusions or both. Previously, Russell et a150 had also pointed to the finding that children experience and report the same positive symptoms of schizophrenia as do adults. McKenna, et a143reviewed the first 71 cases of presumed schizophrenia referred to the National Institute of Mental Health (NIMH) for admission to research studies. Their major point was that there is excellent diagnostic agreement between research clinicians concerning diagnosis of psychotic disorders. For schizophrenia, the agreement was highly statistically significant. Another point emerged from their analysis of diagnosis-a number of presumed schizophrenic young people did not meet diagnostic criteria, but were reliably assessed as having multidimensional impaired disorder. Even though numerous current investigators note the ability to utilize objective diagnostic criteria in children and adolescents, not all psychotic disorders fulfill criteria for schizophrenia. Carlson, et a17 now have reported on the reliability of assessing psychosis in young people, although her group’s sample is a firstepisode patient group with only a portion being teenagers. In an assessment of all first-episode hospitalized psychotic patients, the identification of psychotic symptoms was reliably assessed. In the most recent study of first-episode patients, the authors point out that in the 1990s,
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community-based clinicians accurately make the differential diagnosis between schizophrenia and bipolar illness. Outcome studies can lead to important clinical as well as scientific data about schizophrenia. In a study of adolescent inpatients, Welner and colleagues61were able to assess 13 schizophrenic patients from a larger general population and to note a generally severe outcome. Of the 13 schizophrenic patients, 2 had committed suicide in the 8 to 10year follow-up period. In the remaining 11, social relationships did not develop well and vocational functions were invariably poor. These findings, although on a very small sample, point to a hypothesis of poorer outcome in this early onset group. In a larger sample studied by Krausz and Miller-Th~msen~~ in Germany, adolescent-onset patients were assessed at 5 and 11 years. Many were judged to have continuous illness and required substantial care. Of importance for clinicians was the finding that anxiety and suicidality were substantial issues of morbidity. In this report, a gender difference in adolescents was found, as females had a better outcome than males. In a recently published, long-term outcome study of childhood onset schizophrenia, Eggers and BunkI2 report on a 2-year follow-up study. This current report is the second follow-up assessment by the investigators and describes some interesting points for clinicians and researchers. Overall, the general outcome for the childhood-onset patients was poor, for example, 50% of patients were judged to poorly remitted. On the other hand, 25% were noted to be completely remitted. In their paper, insidious onset was significantly associated with poorer outcome, with none of the insidious-onset patients having a remitted outcome. NEUROPSYCHIATRIC RESEARCH
Noninvasive methods for studying brain structure and function have led to an increased but still a small body of research in the early stages of schizophrenia. Briefly stated, structural brain imaging in adults with schizophrenia have shown increased size of ventricles when compared with nonschizophrenic adult controls. This was originally reported by Johnstone et a130 and reviewed in metaanalysis by Elkis et al,I3 and decreased brain volume (see Ward et a158for review). Also, in adults, follow-up scanning studies have shown that ventricle size does not change over periods of 1-5 years.44,27 However, in the last year, studies of first-break young adultsl0 and childhood-onset schizophrenia patient~ have ~ ~ shown subtle changes in ventricular size during the followup period. As noted in the introduction, the neuropsychiatric study of schizophrenia during adolescence may add to a better understanding of the disease because of important neurodevelopmental events that occur during this period. Further, as more studies are performed, those in the field may learn about specific clinically relevant issues related to schizophrenic teenagers.
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Beginning with brain imaging in adolescents Schulz et al5I decided to approach the issue of onset of ventricular enlargement in schizophrenia by using CT and compared ventricular brain ration (VBR) in patients with that of medical controls and personality disorder patients. The teenage schizophrenic patients, who had an average age of 16 years and had been ill for less than 2 years, had greater VBR compared with both medical record controls and borderline personality patients. Following an analysis by Weinberger et a160 in which they demonstrated that ventricular size was not related to the length of illness, Schulz et a151showed that VBR in teenagers was not related to how long an adolescent patient had been ill. This finding supports the neurodevelopmental hypothesis of schizophrenia as opposed to a neurodegenerative theory in the younger patient group. Research in schizophrenia at the time of CT studies focused on correlates of increased VBR. For example, enlarged VBR was associated with low levels of neuropsychologic function2*and with poor premorbid adjustment.” To pursue this theme of research in adolescents, Jennings et alZ8showed that VBR in teenagers was statistically significantly inversely correlated with metabolites of dopamine (HVA-homovanillic acid) and serotonin (5HIAA-5 hydroxyindole acetic acid), as had been demonstrated by Potkin et a146in adult patients. Also, and of possible clinical relevance, adolescent schizophrenic patients who had enlarged ventricles showed poorer response to antipsychotic medication treatment than adolescents who had ventricles of similar size to the adolescents in the control Note that there are many reports of the relationship of treatment response and brain-imaging parameters-some note a statistical relationship, whereas others do not. Friedman et all9 have done a complete metaanalysis of brainscan studies and neuroleptic treatment outcome and have demonstrated that the relationship is not universal. However, when the illness duration and age of onset were examined, there was a relationship of effect size in the VBR-treatment response correlation. Friedman and colleague^^^ speculate that early stages of schizophrenia may be a time of the illness when brain structure and pharmacologic treatment response are related. With the emergence and availability of MR imaging, our group and that of the NIMH Intramural Program (Dr Judith Rapoport) embarked on studies of adolescent patients. Although each group had examined teenage patients, the NIMH group has focused on childhood-onset patients while the Case Western Reserve University (CWRU) group has studied an adolescent clinical sample from local referrals. From NIMH, Frazier et all6 demonstrated a smaller brain volume and smaller midsagittal thalamic area in the 21 patients compared with the 33 nonpatient controls. Interestingly, the childhood-onset patients had larger VBR than controls, but the difference did not reach statistical significance ( P = 0.06). The authors comment on the importance of studying childhood-onset schizophrenia as it may be a more severe form of the illness and thus biological leads may be more clearly and homogeneously seen. The results outlined in this paper also led the authors to reaffirm their ideas of the continuum of schizophrenia across age groups.
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After the publication of this paper, Dr. Rapoport presented fascinating data on a 2-year follow-up of the childhood-onset group, who were first scanned at age 14.47Interestingly, during the 2-year follow-up, it was revealed that there was a slight but significant increase in the ventricular volume of the childhood-onset group when compared with individuals in the control group. This is all the more remarkable because the patients were not at the beginning of their illness-a time when it seems more likely that structural changes could occur. These results point to the possibility of dynamic changes occurring during adolescence-a finding that deserves closer research attention. The CWRU group has been studying a sample of adolescents who have schizophrenia and who had been referred by local clinicians who then participate in MR imaging structural studies, neuropsychologic assessment, and smooth pursuit-eye tracking studies. All are clinically stabilized on medication of the clinician's choice and receive a diagnostic assessment with structured interviews. The control group was carefully assembled from the community and underwent similar assessments and studies. The MR imaging and the neuropsychology studies that have been presented to date are described. Friedman and colleagues18have presented results of the group's initial MR imaging work with the adolescent schizophrenic patients. The most robust finding was the reduced brain volume index noted in the schizophrenic patients. In the Friedman report, similar to the findings of Frazier et a1,16VBR was not different between the schizophrenic patients and the individuals in the control group, but the VBR measures were numerically equivalent. Assessment of the control group showed wide variability, thus pointing to the importance of methodology in collecting normal samples, as has been discussed by Iacono et a1.26The reduced brain volume finding is consistent with the results of a recent metaanalysis of brain volume that shows a significant reduction of volume across Structural brain studies are an important way to assess the central nervous system in schizophrenia, but they do not directly address function. Kenny et a135reported on the neuropsychologicalresults in the same teenage sample. They noted decreased neuropsychologic performance in the areas of attention, recall, and memory. Interestingly, the patients were not abnormal on all tests. The investigators went on to examine the data, controlling statistically for IQ and attention, and the differences remained, even though the patients had numerically lower IQ scores. Previous studies had pointed to reduced neuropsychologic performance in teenagers-studies such as those by Goldberg et a1,2O which demonstrated significant differences in both verbal and performance IQs in schizophrenic adolescents, pointing to low neuropsychologic performance in this young population. These findings are consistent with the emerging literature, demonstrating either neuropsychologic or neuromotoric differences or both between youngsters who become schizophrenic and youngsters who do not develop schizophrenia used as controls.32 Such findings coupled with neuropsychologic results in young-adult
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first-episode patients4 make Kenny and colleague'^^^ current study in adolescents consistent with results in adults. These imaging and neuropsychologic findings have important implications for the current hypotheses about the pathophysiology of schizophrenia. One of the current and compelling theories of the pathophysiology of schizophrenia is the neurodevelopmental hypothesis.57,59 The theory posits that a lesion (an abnormality, not necessarily, spaceoccupying tissue) interacts with the developing brain. This theory is consistent with an increased VBR, a general lack of gliosis, and a lack of progression of brain-imaging findings (i.e., progressive enlargement of ventricles). The findings of Friedman et all8 and Frazier et all6 of decreased brain volume supports the characteristics of a neurodevelopmental versus a neurodegenerative illness, especially when seen without increase in ventricular size. The CWRU group, however, has not conducted systematic follow-up imaging studies that would assess possible structural changes. Note, as reported by Rapoport et a147the findings that subtle ventricular changes are seen over 2 years. Therefore, the research study of schizophrenia in patients under age 18 can offer unique opportunities for understanding the neurodevelopmental hypothesis. Also, as follow-up studies progress, those in the field can learn if earlyonset disease is more severe as measured by brain imaging. PHARMACOTHERAPY
As noted in previous reviews,15there is a paucity of empiric studies of medication treatment for schizophrenia in adolescents. In children and adolescents, there are 2 placebo-controlled trials45,54 that demonstrate that the traditional antipsychotic medications are effective compared with placebo and that, as expected, positive symptoms are reduced. There is one study using objective ratings that compares two traditional antipsychotic medications-thiothixene and thioridazine,48 and that demonstrates a decrease in psychotic symptoms. An interesting clinical note in Realmuto and colleague^^^ work is the observation of the high rate of neuroleptic intolerant patients-those patients who had intolerable side effects at doses below what would be considered an adequate trial. For many reasons, including efficacy in adult patients and lower movement side effects, investigators have been examining new or atypical antipsychotic medications in adolescents. As expected, early reports were case studies showing the safety and effectiveness of ri~peridone.~~ For this early risperidone case series, the authors note effectiveness in schizophrenia as well as other psychotic disorders. They further suggest that risperidone may help adolescents who were not helped by traditional antipsychotic medications. However, clinicians need to be aware that there is not a controlled trial of the usefulness of risperidone in adolescent nonresponders, although Bondolfi, et a15 have shown the usefulness of risperidone in adult nonresponders.
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Grcevich and colleague^^^ at CWRU recently published a larger case series (N = 16) assessing risperidone treatment in adolescents. In this report, the total BPRS as well as the negative symptom items were both reduced. They found that the medication was well accepted by the young patients, a phenomenon not seen with traditional antipsychotics (note earlier comments re: Realmuto et a1 studys). Note that the Grcevich et alZ3study was started shortly after risperidone was made available so that doses of 6 mg/day were considered routine. Since the completion of the study, our group begins at low doses of risperidone and increases the dose slowly-many of our patients are managed with 3 mg/day. In relation to dosing strategies used for young patients, Kapur and coll e a g u e ~have ~ ~ reported clinical success using haloperidol at a dose of 2 mg/day in first-episode patients. Haloperidol 2 mg leads to high-dopamine receptor blockade as measured by positron emission tomography (PET). Noted that, although there is enthusiasm for the use of risperidone in children and adolescents, Mandoki40 has reported that he frequently saw extrapyramidal symptoms (EPS) in patients having a variety of psychiatric disorders and who were given risperidone. Also, dystonia and galactorrhea were seen. Therefore, it is prudent for clinicians to be aware of these side effects and to follow reports of atypical antipsychotics to be knowledgeable about their safety. Clozapine has been available for many years following the report from Kane et a133 on its usefulness as a treatment for patients who were not responsive to traditional antipsychotic medication treatment. Clozapine is also used for patients who are intolerant to traditional antipsychotic medications and for those who have developed tardive dy~kinesia.~~ The use of clozapine in patients who are under 18 has not received much attention in the literature, perhaps because of the agranulocytosis side effect or general concerns about using a last-resort medication in young people. However, NIMH has explored the use of clozapine in its childhood-onset sample in two distinct studies. The first was a report on the effectiveness and safety in an open trial lasting 6 weeks in which 11 adolescents with childhood-onset schizophrenia were studied.17 The patients had not done well with traditional antipsychotic medication; however, with clozapine, half showed a marked improvement. The authors note that all 11 patients were discharged on clozapine. The mean dose for this group, whose average age was 14.0, was 370 mg/ day-comparable with or slightly lower than doses used in adult clinics. In this open report, the authors note that clozapine was generally well tolerated with side effects being similar to what would be expected in adults. From the same group, Kumra et a137published the results of a double-blind, haloperidol-controlled trial in childhood-onset patients ( n =21) who were approximately 14 years old at the time of the trial. Clozapine showed clear statistical advantages over haloperidol on measures of psychosis. However, in some contrast to their open-label report,
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one third of the patients had clozapine discontinued-both neutropenia and seizures were the most significant concerns. An open-label study from Israel56of clozapine showed improvement in positive and negative symptoms of schizophrenia in a childhoodonset group. Interestingly, a lower dose of medication-mean dose of 227 mg/day compared with 370 mg/day-was used in this young group as reported by Frazier et al.17 The overall report was positive and no agranulocytosis was noted. Perhaps strategies to reach the lowest effective dose of clozapine could lead to successful treatment with few side effects. Preliminary reports indicate that tardive dyskinesia (TD) may be seen less frequently with risperidone6 and with the potential for low TD with olanzapine exists based on early ~tudies.’~” As young people diagnosed as schizophrenic may be exposed to antipsychotic medication for many years, these two new medications may reduce the risk of TD when used as the first treatment. There are important issues related to pharmacotherapy that have been brought into focus by studies of first-break schizophrenic patients and that have a bearing on the treatment of adolescent schizophrenic patients. Johnstone et aP1 noted an association between the length of time a patient was ill and their course following initial treatment. This report was followed by the assessment by Loebel et a138of the relationship between the length of time a patient had been ill and the treatment response in the Hillside first-episode study. The reports build on earlier follow-up studies. One study was done by May et a141and it showed an increase in hospital days for patients assigned to placebo as opposed to those who were assigned to medication, and the other was a review by Wyatt62in which the issues of early medication use and outcome were discussed. For children and adolescents who have schizophrenia, if a chronic course is to be avoided, it may be important to be more assertive in beginning medication treatment than was thought in the past. It can be hoped that the new, atypical antipsychotic medications will allow for a better and safer start with treatment. FAMILY ISSUES
Over the past 20 years, many paper^'^,^^ have noted an improvement in patient outcome, usually measured in reduced relapse rates, when family therapy is part of the treatment regimen. Review of the family therapy studies reveals that most interventions are based on a psychoeducational and supportive model such as those described by Anderson’ and M ~ F a r l a n e Therefore, .~~ one would reason that such interventions could help childhood-onset and adolescent schizophrenic patientsmaybe especially, because they are generally living at home. Interestingly, there is little empiric literature that addresses family concerns (or burdens) of this patient age group. Also, there are no empiric trials, comparable with adult studies, that provide assistance in
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how to proceed with family psychoeducational programs for adolescent patients. We were struck by the families’ response to the onset of psychosis in their adolescent children as we began working with them in our adolescent brain-imaging project. Somewhat unlike families of adult patients, these younger families responded (in general) with shock, denial, and anger. These responses are, perhaps, more similar to a family’s response to a serious medical illness. To address this issue, Davies9 has reported on preliminary results of data gathered from over 50 family members who have an adolescent who has a serious psychiatric illness. She reported substantial burden that, unsurprisingly, was not evident among all families. They conclude that assessment of burden and a family’s own difficulties (i.e., with depression) can lead to specific treatment planning for the family. It goes without saying that studies with appropriate controls are needed to develop the most constructive treatment approaches.
CONCLUSION
In this article from a neuropsychiatric viewpoint, attention has been drawn to issues facing patients who have schizophrenia. Therefore, it contains descriptions of studies that illustrate the frequency of schizophrenia before adulthood. The view is that, although childhood-onset of schizophrenia may be rare, adolescent-onset schizophrenia is not. Perhaps because adolescents quickly become adult patients, less attention has been focused on developing empiric neurobiologic studies for this patient group. However, as has been noted in the work by NIMH, the younger-onset patient group may offer scientific opportunities because they are hypothesized to be a more homogenous subtype of schizophrenia. Also, the follow-up studies-the few that have been performedshow that early-onset patients may be more severely ill than adult-onset patients, thus clinicians need more information on the characteristics of the child and the adolescent group. The studies cited in the section on brain-imaging demonstrate that brain morphometric differences from controls-smaller brain volume, for example-are present in the adolescent group. Researchers studying this population indicate that this adds to theories that childhood and adolescent schizophrenia are on a continuum with the adult disorders, not a separate illness. Most recently though, Delisi et all0 and Rapoport et a147have indicated that there may be morphometric changes at first break and in childhood-onset schizophrenia. Thus, studies of adolescents when important brain developments events occur gain new importance. Neuropsychology studies have considerably added to the understanding of those in the field of adult schizophrenia-both in characterization and in relationship to functional outcome.24In a report by Kenny et aP5 it was demonstrated that brain function-as assessed by neuro-
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psychology-is poorer in teenage patients. Such studies can help investigators understand schizophrenia better by charting neuropsychologic measures through the life cycle, and this may hold greater importance for clinicians. As expected, not all adolescents have the same neuropsychologic deficits so that understanding which deficits are prominent may lead to improved treatment planning. New, atypical antipsychotic medications may have much to offer adolescent patients, and we have noted the preliminary studies exploring both clozapine and risperidone. Our view is that the new drugs may treat psychosis with fewer side effects than seen with traditional antipsychotics, thus allowing for a better start with treatment. Despite enthusiasm for new treatments, there is still little empiric work on their use, so caution is still advised. We note the accumulating evidence of the relationship between length of time before treatment and outcome and urge clinicians to help young people get started with pharmacotherapy more quickly after the onset of psychosis. The focus on neuropsychiatric parameters does not exclude the importance of family treatment both to diminish their own distress and to improve the patient’s outcome. However, we must note that little of the work performed with adult patients and their families has found its way into the research on adolescents. Our impression has been that young families have distinct needs as they face the shock of onset of a psychotic illness in the family. In conclusion, we have aimed to describe the epidemiology, diagnostic factors, neurobiologic characteristics and treatment considerations for childhood and adolescent schizophrenic patients. We think we have demonstrated the existence of compelling evidence for continuity in phenomenology and pathophysiology between adolescent and adult stages of the illness and the importance of early intervention. Clearly, this is an emerging area of schizophrenia research and program development so that those interested in these young patients have much to look forward to in upcoming literature. References 1. Anderson C: A psychoeducational program for families of patients with schizophrenia. In McFarlane WR (ed): Family Therapy in Schizophrenia. New York, Guilford Press, 1983 2. American Psychiatric Association: Diagnostic and Statistical Manual of Mental Disorders, ed 3. Washington, DC, American Psychiatric Association, 1980 3. Beiser M, Erickson D, Fleming JAE, et al: Establishing the onset of psychotic illness. Am J Psychiatry 150:1349-1354, 1993 4. Bilder RM, Lipschutz-Broch L, Reiter G, et al: Intellectual deficits in first-episode schizophrenia: Evidence for progressive deterioration. Schizophr Bull 18:437448,1992 5. Bondolfi G, Bauman P, Petris M, et al: A randomized double-blind trial of risperidone versus clozapine for treatment-resistant chronic schizophrenia. 151st Annual Meeting of the American Psychiatric Association, Miami, May 1995 6. Brecher MB: Long-term safety of risperidone [abstract NR3771. New Research Annual Meeting of the American Psychiatric Association, New York, 1996, p 170
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